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Targeted T cells are emerging as effective non-toxic therapies for cancer. Multiple elements, however, contribute to the overall pathogenesis of cancer through both distinct and redundant mechanisms. Hence, targeting multiple cancer-specific markers simultaneously could result in better therapeutic efficacy. We created a functional chimeric antigen receptor'the TanCAR, a novel artificial molecule that mediates bispecific activation and targeting of T cells. We demonstrate the feasibility of cumulative integration of structure and docking simulation data using computational tools to interrogate the design and predict the functionality of such a complex bispecific molecule. Our prototype TanCAR induced distinct T cell reactivity against each of two tumor restricted antigens, and produced synergistic enhancement of effector functions when both antigens were simultaneously encountered. Furthermore, the TanCAR preserved the cytolytic ability of T cells upon loss of one of the target molecules and better controlled established experimental tumors by recognition of both targets in an animal disease model. This proof-of-concept approach can be used to increase the specificity of effector cells for malignant versus normal target cells, to offset antigen escape or to allow for targeting the tumor and its microenvironment.

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.

Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.

Cancer cells can live and grow if they succeed in creating a favorable niche that often includes elements from the immune system. While T lymphocytes play an important role in the host response to tumor growth, the mechanism of their trafficking to the tumor remains poorly understood. We show here that T lymphocytes consistently infiltrate the primary brain cancer, medulloblastoma. We demonstrate, both in vitro and in vivo, that these T lymphocytes are attracted to tumor deposits only after the tumor cells have interacted with tumor vascular endothelium. Macrophage Migration Inhibitory Factor (MIF)\" is the key chemokine molecule secreted by tumor cells which induces the tumor vascular endothelial cells to secrete the potent T lymphocyte attractant \"Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES).\" This in turn creates a chemotactic gradient for RANTES-receptor bearing T lymphocytes. Manipulation of this pathway could have important therapeutic implications.

Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d , a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments. A short hairpin RNA screen to identify genes that modify the action of tumour-infiltrating CD8 T cells in tumour-bearing mice pinpointed the phosphatase subunit Ppp2r2d as a new target for tumour therapy; knockdown of Ppp2r2d in T cells enabled their accumulation in tumours and significantly delayed tumour growth. New targets for cancer immunotherapy Immunotherapy is an important area of cancer research, and recent work has shown that targeting inhibitory receptors on T cells can result in clinical benefit in patients with advanced cancers. A major problem in the field is the difficulty of finding potential targets. Here Kai Wucherpfennig and colleagues show that in vivo discovery of therapeutic targets is a practical proposition by using short hairpin RNA (shRNA) screening to identify genes that modify the action of tumour-infiltrating CD8 T cells in tumour-bearing mice. They identify the regulatory phosphatase Ppp2r2d as a target and show that knockdown of Ppp2r2d in T cells enabled their accumulation in tumours and significantly delayed tumour growth.

Voices of Emancipation seeks to recover the lives and words of former slaves in vivid detail, mining the case files of the U.S. Pension Bureau, which administered a huge pension system for Union veterans and their survivors in the decades following the Civil War. The files contain an invaluable, first-hand perspective of slavery, emancipation, black military service, and freedom. Moreover, as Pension Bureau examiners began interviewing black Union veterans and their families shortly after the Civil War, the files are arguably among the earliest sources of ex-slaves reflecting on their lives, occurring decades before better-known WPA Slave Narratives of the 1930s took place. Voices of Emancipation explores the words of former slaves topically, beginning with recollections of slavery, moving on to experiences of military service in the Civil War, the transition to freedom, and finally to reflections on marriage and family before and after emancipation. With an introduction that places the pension files in context and presents the themes of the book, and historical commentary interwoven throughout the excerpts of the interviews themselves, Elizabeth A. Regosin and Donald R. Shaffer effectively introduce the files and the treasures they contain to students and general readers, but also provide specialists with an indispensable research tool.

Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR’877), a potentially novel PD-1–targeted immunocytokine that fuses a high-affinity anti–PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1 + T cells, enhancing proliferation and activation of antigen-experienced CD8 + and CD4 + T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR’877 activates STAT5 signaling in PD-1 + lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR’877 accelerated viral clearance and induced robust antitumor immunity by expanding cytotoxic CD8 + T cells and promoting Th1 polarization. Notably, SAR’877 outperformed anti–PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR’877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.

Epstein-Barr virus-associated lymphoproliferative diseases (EBV-LPD) after hematopoietic stem cell transplantation or solid-organ transplantation remain a serious and potentially life-threatening complication. In the last decade, outcomes for EBV-LPD have significantly improved. Key to this success was the development of early detection methods, such as serial measurements of EBV-DNA load in the peripheral blood of transplant recipients. Immunotherapeutic interventions for EBV-LPD include reduction of immunosuppression, CD20 monoclonal antibodies (rituximab) as monotherapy or in conjunction with chemotherapy, and adoptive immunotherapy with EBV-specific T cells. Pre-emptive immunotherapeutic interventions can prevent the development of EBV-LPD. As monotherapy, immunotherapy is effective in inducing remissions of EBV-LPD with low-risk features. For high-risk disease, combining immunotherapy with conventional therapies has led to superior outcomes. Current challenges consist of risk stratifying patients so that patients receive the most efficacious therapy without suffering from unwanted side effects.